Arthritis is a degenerative joint disease currently more than 46,000,000 individuals in the United States. Typical clinical symptoms are pain and stiffness, particularly after prolonged activity. In industrialized societies arthritis is the leading cause of physical disability, increased health care usage, and impaired quality of life. The impact of arthritic conditions is expected to grow as the population both increases and ages in the coming decades.
Despite the prevalence of arthritic diseases, their precise etiologies, pathogenesis, and progression are not well understood. Mounting evidence suggests that inflammatory cytokines and growth factors play a central role in the progression of arthritis. The destruction of the extracellular matrices of articular cartilage and bone in arthritic joints is thought to be mediated by excessive cytokine activities and imbalance between inflammatory cytokines and their natural antagonists. The identification of molecules that modulate signaling by arthritis-related cytokines is therefore highly relevant to the prevention and treatment of arthritis.
Tumor necrosis factor-α (TNF-α) is a key mediator of cytokine-induced inflammation in arthritis. Progranulin (PGRN) is a secreted glycoprotein shown to play an essential role in cartilage formation (See Xu, K, et al. (2007) J Biol. Chem. 282(15):11347-11355; WO 2008/094687 A2). PGRN has been shown to bind specifically to TNF receptors 1 and 2 (TNFR1, TNFR2) and to antagonize TNF-α signaling. It has been previously shown that peptides derived from human PGRN are effective in the treatment of arthritis in murine models.